Received 12/10/2019 Review began 12/12/2019 Review ended 12/12/2019 Published 12/15/2019

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Epidermolysis Bullosa Acquisita: A CaseReport of a Rare Clinical Phenotype and aReview of LiteratureCristina Beiu , Mara Mihai , Liliana Popa , Tiberiu Tebeica , Calin Giurcaneanu

1. Oncologic Dermatology, Elias Emergency University Hospital, Carol Davila University of Medicine andPharmacy, Bucharest, ROU 2. Dermatopathology, Dr. Leventer Centre, Bucharest, ROU

Corresponding author: Cristina Beiu, cristina.popescu@drd.umfcd.ro

AbstractEpidermolysis bullosa acquisita (EBA) is an autoimmune subepidermal bullous disorder of theskin and mucous membranes. The disease results from the production of immunoglobulin G(IgG) antibodies against type-VII collagen, a major component of anchoring filaments in thedermal-epithelial junction. The disease has two major forms of presentation: the classical(non-inflammatory) type and the inflammatory type. Classical EBA is mainly characterized bythe following features: development of non-inflammatory tense blisters on trauma-proneareas, multiple milia cysts, minimal or no inflammation findings on histopathology.Alternatively, inflammatory EBA is defined by widespread inflammatory blistering eruptionsand a neutrophil-rich inflammatory infiltrate on standard histopathology. In both cases,specialized immunopathological findings are further required to establish an accuratediagnosis. In this article, we present an atypical case that shares features of both inflammatoryand non-inflammatory forms of EBA. The case also serves to review and synthesize currentconcepts on the etiopathogenesis, diagnosis, and treatment of this extremely rare disease.

Categories: Dermatology, Internal Medicine, PathologyKeywords: epidermolysis bullosa acquisita, blistering disorders, bullous diseases

IntroductionEpidermolysis bullosa acquisita (EBA) is an acquired, subepidermal mucocutaneous blisteringdisorder that results from autoimmunity to collagen VII, a main structural component ofanchoring fibrils in the basement membrane zone (BMZ) of the dermal-epidermal junction(DEJ). The incidence of this rare disease is approximated at 0.2 per one million people and itusually affects middle-aged adults [1]. Anecdotally, the disease exhibits two main clinical andhistopathological forms: non-inflammatory (also called "classical form") and inflammatoryEBA, the latter mimicking other subepithelial autoimmune blistering disorders [2].

This case illustrates an atypical clinical phenotype of EBA presenting with specific clinicalfindings of the classical form but with unequivocal histopathological features of inflammatoryEBA. The case also serves to review classic and unexpected findings of the etiopathogenesis,diagnosis, and treatment of this extremely rare disease.

Case PresentationA 54-year-old Caucasian male presented to our dermatology department for the evaluation of amucocutaneous blistering eruption that had evolved over a period of three years. The eruptionconsisted of tense blisters that easily rupture to form painful erosions (Figure 1). Some of the

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Open Access CaseReport DOI: 10.7759/cureus.6386

How to cite this articleBeiu C, Mihai M, Popa L, et al. (December 15, 2019) Epidermolysis Bullosa Acquisita: A Case Report of aRare Clinical Phenotype and a Review of Literature. Cureus 11(12): e6386. DOI 10.7759/cureus.6386

https://www.cureus.com/users/105162-cristina-beiuhttps://www.cureus.com/users/139754-mara-mihaihttps://www.cureus.com/users/139753-liliana-popahttps://www.cureus.com/users/141512-tiberiu-tebeica-https://www.cureus.com/users/139755-calin-giurcaneanu

older erosions had already healed with small atrophic scar areas and multiple milia cysts(Figure 2). The patient had complaints of increased skin fragility stating that the lesions wereeasily induced by minor injuries. The lesions were widespread but indeed had a predilection forareas that are regularly prone to repetitive trauma: palmoplantar area, elbows, knees, andposterior trunk. Physical examination additionally showed onychodystrophy with partial loss ofthe big right toenail (as seen in Figure 3) and moderate fibrosis of the fingers, with reducedhand mobility (Figure 4). The patient also suffered from concomitant mucosal involvement,with multiple oral erosions (Figure 5).

FIGURE 1: Clinical image illustrating tense blisters (blackarrows) and multiple erosions (green arrows) on the right palm

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FIGURE 2: Multiple milia cysts (yellow asterisk) developed onan older lesion on the elbow

FIGURE 3: Marked onychodystrophy of the big right toenail(white arrow)

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FIGURE 4: Fibrotic changes of the fingers; please notice theshiny and thickened aspect of the skin (white arrows)

FIGURE 5: Mucosal erosions on the palate (white arrows)

Prior to referral in our clinic, the patient was initially diagnosed as having bullous pemphigoid

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(BP). A review of the patients' previous medical records showed that the diagnosis was based ondirect immunofluorescence studies of a biopsy section which revealed the depositionof immunoglobulin G (IgG) and C3 at the DEJ in a linear pattern.

We performed a comprehensive metabolic panel which was within normal limits. Pemphigoidcirculating antibodies (BPAG 180 and BPAG230) and antinuclear antibodies (ANA) were allnegative and C3 and C4 were within the normal range. An esophago-gastro-duodenoscopyshowed extensive erosions on pharyngeal and upper-esophagus mucosa. No stricture orstenosis was detected. A colonoscopy was also performed but no signs of inflammatory boweldisease were detected. A thorough review of systems was entirely negative.

Two 4-mm punch biopsies were taken, one lesional for hematoxylin and eosin (H&E) and oneperilesional for direct immunofluorescence (DIF). Standard histopathology with H&E showedsubepidermal blistering with a neutrophil-rich infiltrate in the papillary dermis and within thebullous lesions. Mononuclear cells such as lymphocytes and monocytes could also be observed.Discrete fibrous changes of vascular hyperplasia were present in the superficial dermis,representing the histopathological correlation of the clinical scarring (Figure 6).

FIGURE 6: Microscopy image (Hematoxylin and Eosin staining)showing subepidermal blistering and a neutrophil-rich infiltratein the papillary dermis and within the bullous lesion

Direct immunofluorescence tests showed linear deposits of IgG and C3 at the DEJ. IgA testednegative. Fibrinogen was positive in the cleavage area (non-specific finding). The "salt-splitskin" technique showed the localization of the immunoreactants, mainly IgG, along the dermalside of the artificially induced blisters at the level of lamina lucida (Figure 7).

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FIGURE 7: Studies on “salt-split skin” demonstrated lineardeposits of the immunoreactants, mainly IgG, on the dermalside of the dermo-epidermal separation, at the base of thebullae

These findings supported the clinical diagnosis of EBA. We initiated treatment with 50 mg ofdapsone per day. This resulted in decreased formation of new blisters. However, disease activityhas persisted.

DiscussionThe two most common forms of EBA are: (1) the classical (non-inflammatory) type and (2) theinflammatory type, subsequently divided into various subtypes: (i) BP-like EBA; (ii) clinicallymimicking cicatricial pemphigoid-like; (iii) linear IgA bullous dermatosis (LABD)-like; (iv) andBrunsting-Perry pemphigoid-like. The two most common presentations are the classical non-inflammatory EBA and the BP-like EBA [2].

The classical form is characterized by tense blisters and erosions without clinically associatedinflammation. It is usually localized towards trauma-prone areas. Millia and scarring arecommon findings. In severe cases, nail loss, fibrosis of the fingers and esophageal stenosis may

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occur. In contrast, the inflammatory form is characterized by vesiculobullous disseminatederuptions with a predilection for the trunk, intertriginous areas, and extremities. The tensebullae develop on erythematosus, inflamed basis [3]. Mucosal lesions are frequent in bothclassical and inflammatory EBA and both ocular and gastrointestinal mucosa can be affected invarious degrees [4].

From the clinical features, we initially considered our patient as having classical non-inflammatory type EBA. But histopathology showed numerous neutrophils within thesubepidermal blisters as well as in the interstitial infiltrate, pointing towards an inflammation-rich form [5]. Considering both the clinical and histopathological aspects, we hypothesized thatour patient suffered from an atypical form of EBA, a mixed form that seems to have resultedfrom an overlap between the classical and the inflammatory forms. A possible explanation forthis mixed clinical phenotype would be the epitope spreading phenomenon that has beenextensively investigated in autoimmune skin diseases. Numerous epitopes on the N-terminaldomain of type VII collagen are identified by circulating autoantibodies in patients with EBAand reactivity with various epitopes can induce different clinical phenotypes [2,6].

While clinical and standard histopathological findings can be characteristic for EBA, theycertainly are not specific and additional testing is required. The diagnosis can be narroweddown with the aid of direct immunofluorescence (DIF) testing for tissue-bound autoantibodies.This involves immunofluorescence labeling of antibodies. On DIF, we basically tag the patient’sautoantibodies on tissue sections and this would show linear deposition of IgG and oftenC3 along the BMZ. But this is still a non-specific finding, as it can be seen in BP as well as anumber of other subepidermal autoimmune blistering disorders [7].

So the best next test to perform would be immunofluorescence on BMZ-split skin. Perilesionaltissue is incubated with 1 mol sodium chloride (1 M NaCl) and induces an artificial split(cleavage) at the level of lamina lucida, a particularly vulnerable area of the basementmembrane. Subsequent binding of autoantibodies on the dermal or epidermal side of theinduced bullae helps refine and narrow the differential diagnosis [8].

When we consider the anatomy of the basement membrane, collagen VII is located at thebottom, as part of the anchoring fibrils, underneath lamina densa and lamina lucida. So, weexpect that the target of the autoantibodies involved in EBA would be below the lamina lucida,resulting in a linear deposition of IgG and potentially C3 at the base of the artificially inducedsalt-split skin (on the dermal side). This can also be seen in some forms of mucous membranepemphigoid, as well as bullous systemic lupus erythematosus (SLE) so additional tests may berequired if the later disorders are suspected [9-10]. In contrast, in BP, which is often the primarydifferential diagnosis for EBA, linear deposits of IgG are seen on the roof of the induced blister(on the epidermal side) or on both the dermal and epidermal side simultaneously [10].

The "salt-split skin" technique can be performed by utilizing perilesional skin (DIF), as in ourpatient’s case, or by using serum from the patient and a salt-split human skin as a substrate(indirect immunofluorescence). A drawback for the use of IIF is represented by the fact thatsome patients may have low serum levels of type VII collagen antibodies, resulting in false-negative test results [11].

In our case, and most of the cases in general, the diagnoses of EBA can be established throughthe correlation between the clinical findings, pathological features and immunoreactivitypattern in the "salt-split skin" technique [3]. On a research basis, additional testing is availableto further differentiate EBA from other rare sub-lamina-densa blistering diseases. Examples ofsuch tests are: (I) Transmission electron microscopy -shows the blister cleavage below thelamina densa and also a decrease in anchoring fibrils at that level [12]; (II) Enzyme-linked

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immunosorbent assay (ELISA) - a quantitative test that can detect and also monitor the level ofcollagen VII autoantibodies specifically [13-14]; (III) Direct and/or Indirect Immunoelectronmicroscopy (IEM) - these tests can provide highly precise ultrastructural location of IgGdeposits in the perilesional skin. The IgG antibodies are previously labeled with colloidal goldor peroxidase and then appear as electron-dense deposits on the anchoring fibrils [15].

As shown in our case, EBA itself can cause considerable morbidity. But it can also be associatedwith a variety of systemic conditions such as Crohn’s disease, SLE, or several endocrinopathies[16]. Inflammatory bowel disease (IBD) is the most common associated disease. A possibleexplanation is that type VII collagen is also expressed on the basement membrane of thehuman colon and autoantibodies against type VII collagen were found in some patients withIBD [17]. Therefore, it’s important to have a high level of suspicion if patients have a positivereview of systems beyond the skin.

When it comes to treatment options for EBA, data are limited. Because it is a very rarecondition, there is a lack of well-designed or large studies such as randomized control trialsinvestigating treatment options for this condition. So we’re left with a handful of case reportsto help guide treatment decisions. Often empiric treatment is tried with patients and differentmedications are introduced in a stepwise approach depending on the patient’s response.Unfortunately, the disease tends to be fairly refractory to treatment but the inflammatory formsdo tend to do a little bit better [16].

Long-term systemic glucocorticoids have proven to be less effective for EBA than for otherblistering disorders. Some improvements have been documented with immunosuppressiveagents [18]. For the previous three years, our patient had received treatment with oralglucocorticoids and systemic immunosuppressive medications, including azathioprine,cyclosporine or methotrexate, with no significant improvement. Thus, we preferred a differentapproach to initial therapy. We initiated treatment with dapsone, since treatmentrecommendations for most patients consist of colchicine or dapsone, in monotherapy or incombination [18-19]. For patients with EBA refractory to colchicine and dapsone, rituximab, ananti-CD20 monoclonal antibody, is a promising option but the high costs represent a majorbarrier in the use of these agents for patients with EBA [14].

A curative treatment for EBA does not currently exist. Hence, the goal of treatment is long-termremission of the disease. It usually has a prolonged course [18].

ConclusionsWe conclude that in the case of EBA, and in other rare diseases in general, current knowledgecould be enriched with the discovery of additional clinical phenotypes that at the moment maybe under-diagnosed or under-reported in the literature. Further studies will be required toclarify whether our findings are simply hypothetical or purely incidental, or if EBA is indeed adisease with further various subtypes to be unraveled and well-established.

Additional InformationDisclosuresHuman subjects: Consent was obtained by all participants in this study. Conflicts of interest:In compliance with the ICMJE uniform disclosure form, all authors declare the following:Payment/services info: All authors have declared that no financial support was received fromany organization for the submitted work. Financial relationships: All authors have declaredthat they have no financial relationships at present or within the previous three years with anyorganizations that might have an interest in the submitted work. Other relationships: All

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authors have declared that there are no other relationships or activities that could appear tohave influenced the submitted work.

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Epidermolysis Bullosa Acquisita: A Case Report of a Rare Clinical Phenotype and a Review of LiteratureAbstractIntroductionCase PresentationFIGURE 1: Clinical image illustrating tense blisters (black arrows) and multiple erosions (green arrows) on the right palmFIGURE 2: Multiple milia cysts (yellow asterisk) developed on an older lesion on the elbowFIGURE 3: Marked onychodystrophy of the big right toenail (white arrow)FIGURE 4: Fibrotic changes of the fingers; please notice the shiny and thickened aspect of the skin (white arrows)FIGURE 5: Mucosal erosions on the palate (white arrows)FIGURE 6: Microscopy image (Hematoxylin and Eosin staining) showing subepidermal blistering and a neutrophil-rich infiltrate in the papillary dermis and within the bullous lesionFIGURE 7: Studies on “salt-split skin” demonstrated linear deposits of the immunoreactants, mainly IgG, on the dermal side of the dermo-epidermal separation, at the base of the bullae

DiscussionConclusionsAdditional InformationDisclosures

References